EP0500905B1 - Pharmazeutische zusammensetzungen zur aids-behandlung - Google Patents

Pharmazeutische zusammensetzungen zur aids-behandlung Download PDF

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Publication number
EP0500905B1
EP0500905B1 EP91917237A EP91917237A EP0500905B1 EP 0500905 B1 EP0500905 B1 EP 0500905B1 EP 91917237 A EP91917237 A EP 91917237A EP 91917237 A EP91917237 A EP 91917237A EP 0500905 B1 EP0500905 B1 EP 0500905B1
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aids
pharmaceutically acceptable
treatment
acceptable salts
patient
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EP0500905A1 (de
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Stanislaw R. Burzynski
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine

Definitions

  • the present invention relates to the prevention and treatment of diseases caused by retroviruses, particularly AIDS (Acquired Immune Deficiency Syndrome), ARC (AIDS-related complex), and PGL (Persistent Generalized Lymphadenopathy).
  • AIDS Abnormal Immune Deficiency Syndrome
  • ARC AIDS-related complex
  • PGL Persistent Generalized Lymphadenopathy
  • AIDS is a disease characterized by progressive dysfunction of the immune system.
  • T4 and T8 lymphocytes which are the affected cells of the immune system, develop according to the program encoded in the DNA of the cell.
  • the program in DNA also contains the fragment corresponding to viral RNA, which was transcribed through reverse transcriptase.
  • the presence of such a program causes the T4 cell to malfunction and live a much shorter life and T8 cells to multiply more rapidly.
  • the decrease of T4 lymphocyte count and increase of T8 lymphocyte count will cause progressive failure of the immune system manifested by opportunistic infections and neoplastic diseases associated with AIDS, ultimately leading to the patient's death.
  • antineoplastons cell differentiating agents
  • the present inventor postulates that the human body possesses a biochemical defense system consisting of antineoplastons, which are small and medium size peptides and amino acid derivatives (Burzynski, Internat . J . Exp . Clin . Chemother ., 2:63 (1989)).
  • the basis of defense in this system is reprogramming of the cells which contain the wrong program for development.
  • Such theory has been tested in the treatment of cancer by inducing normal differentiation in cancer cells (Burzynski, U.S. Patent Nos. 4,470,970, 4,558,057 and 4,559,325).
  • Antineoplaston A10 was the first active ingredient isolated and synthetically produced (Burzynski et al., Proc . 13 Internat . Cong . Chemother ., Vienna , Austria , 17:P.S.12.4.11-4). Antineoplaston A10, which chemically is 3-phenylacetylamino-2,6-piperidinedione, undergoes enzymatic hydrolysis in human intestine to form phenylacetylglutamine and phenylacetylisoglutamine in the ratio of 4:1. Pharmaceutical formulations of the two digestion products of Antineoplaston A10 was named Antineoplaston A10 injections (Burzynski, Internat . Journal Exp . Clin .
  • US-A-4 705 796 discloses injections comprising 3-N-phenylacetylamino-2,6-piperidinedione.
  • EP-A-O 069 232 discloses pharmaceutical compositions comprising 3-N-phenylacetylamino-2,6 piperidinedione, phenylacetylglutamine or a combination of phenylacetyl glutamine and phenylacetic acid (as a 1:4 mixture) and salts thereof.
  • the present invention provides pharmaceutical compositions for use in treating AIDS containing a therepeutically effective amount of a piperidinedione compound of the formula wherein R is OH, NH2, OW, or H; X is H, F, Cl, Br, I, OH, OW, NO2 or NH2; Y is H, F, Cl, I or Br; W is or a C1 to C12 aliphatic group; Z is an aliphatic or aromatic group of from C1 to C12; X and Y can both vary within the compound; and pharmaceutically acceptable salts thereof.
  • R is OH, NH2, OW, or H
  • X is H, F, Cl, Br, I, OH, OW, NO2 or NH2
  • Y is H, F, Cl, I or Br
  • W is or a C1 to C12 aliphatic group
  • Z is an aliphatic or aromatic group of from C1 to C12
  • X and Y can both vary within the compound; and pharmaceutically
  • compositions containing as an active ingredient the hydrolysis products of formula [I] piperidinediones, namely R,X,Y substituted phenylacetylglutamine; R,X,Y substituted phenylacetylisoglutamine; R,X,Y substituted phenylacetic acid; mixtures thereof; and pharmaceutically acceptable salts thereof.
  • salts mean salts having the biological activity of the parent compound and lacking unusually toxic activity at the selected administration level.
  • Such salts include inorganic sodium, potassium and ammonium salts, organic diethanolamine, cyclohexylamine, and amino acid salts.
  • AIDS-related diseases include AIDS, ARC, and PGL.
  • Antineoplaston AS2-1 (1:4 ratio of sodium salt of phenylacetylglutamine and sodium salt of phenylacetic acid) has been administered for the purpose of treating AIDS-related diseases in the form of 500 mg capsules and 100 mg/ml intravenous infusions.
  • Antineoplaston A10 100 mg/ml (4:1 ratio of phenylacetylglutamine sodium salt and phenylacetylisoglutamine sodium salt) intravenous infusions have also been used in the treatment of AIDS-related diseases and AIDS-related tumors.
  • the piperidinedione compounds of this invention can be prepared by condensation of the appropriate R,X,Y substituted phenylacetic acid derivative with L-glutamine to produce the corresponding R,X,Y substituted phenylacetylglutamine derivative that is then intramolecularly cyclized to the desired 3-(N-R,X,Y substituted phenylacetylamino)-2,6-piperidinedione.
  • the condensation reaction is facilitated by prior activation of the phenylacetic acid derivative with a reagent such as N-hydroxysuccinimide in the presence of DCC (N,N-dicyclohexylcarbodiimide), 2-mercaptothiazoline in the presence of DCC, or DCC alone.
  • the phenylacetylglutamine derivative is also preferably activated before cyclization by reaction with N-hydroxysuccinimide in the presence of DCC or by reaction with 1,1'-carbonyldiimidazole. These reactions are described in more detail in Burzynski, Drugs of the Future , 10(2):103 (1985).
  • Desired R,X,Y substituted derivatives of phenylacetic acid can be purchased commercially or prepared synthetically by methods known to those skilled in the art according to well established rules of electrophilic and nucleophilic aromatic substitution.
  • 4-hydroxyphenylacetic acid which is commercially available from Aldrich Chemical Company, Inc., can be nitrated with dilute HNO3 to produce 4-hydroxy-3-nitrophenylacetic acid that is used as is in the next step of reaction.
  • the nitro group in 4-hydroxy-3-nitrophenylacetic acid can be reduced to the corresponding amine and then reacted with sodium nitrite in acid to form the diazonium salt, that can be converted into a wide range of functional groups, including chloro, fluoro, bromo and hydroxyl.
  • Phenylacetic acid can alternatively be nitrated in the 4-position to produce 4-nitrophenylacetic acid, that is used as is in the reaction or converted to the diazonium salt and derivatized.
  • the nitro group can be reduced to the corresponding amino group as a final step of reaction by methods known to those skilled in the art, including catalytic hydrogenation.
  • Prodrugs of the hydroxyl or amino derivatives of 3-N-phenylacetylamino-2,6-piperidinedione can be prepared by alkylation or acylation of the hydroxyl or amino moieties according to established methods. These protecting groups can be cleaved in vivo or in vitro by the appropriate enzyme, generating the active compound.
  • R,X,Y substituted piperidinediones, R,X,Y substituted phenylacetic acid, and R,X,Y substituted phenylacetylglutamine of the present invention are useful in the treatment of AIDS-related diseases.
  • Pharmaceutical compositions, including these active compounds, can be prepared as described below.
  • the active compound, mixtures of the active compounds, or pharmaceutically acceptable salts thereof, are included in the pharmaceutically acceptable carrier or diluent in an amount sufficient to exert a therapeutic effect, i.e., increasing T4 cell count and decreasing T8 cell count.
  • the active materials can be administered by any appropriate route, for example, orally, parenterally, intravenously, intradermally, subcutaneously, intraperitoneally, or topically, in liquid or solid form.
  • the active compound is included in the pharmaceutically acceptable carrier in an amount sufficient to exert a therapeutically useful effect on the AIDS-diseased patient without serious toxic effect.
  • the therapeutic effect is measured by an increasing T4 cell count, decreasing T8 cell count, and increasing T4/T8 ratio.
  • Normal values for T4 cell count range from 450/mm3 to 1300/mm3.
  • Normal values for T8 cell count are from 250/mm3 to 750/mm3. Normally, the T4/T8 ratio is more than 0.9.
  • the concentration of active compound in the drug composition will depend upon absorption, inactivation, and excretion rates of the active compound as well as other factors known to those skilled in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions.
  • the active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at varying intervals of time. For less advanced cases of HIV infection and AIDS, we are using treatment orally.
  • the patient is given Antineoplaston AS2-1 capsules from 3 to 10 g/day, or 40 mg/kg/24 h to 150 mg/kg/24 h, and preferably, 6 g/day or 85 mg/kg/24 h.
  • Antineoplaston A10 capsules (3-phenylacetylamino-2,6-piperidinedione) can be given from 3 g to 14 g/day or 40 mg/kg/24 h to 200 mg/kg/24 h, preferably 6 g/day or 85 mg/kg/24 h.
  • the dosages of sodium salt phenylacetylglutamine given orally will be five times smaller than AS2-1 capsules, because AS2-1 consists of sodium salts of phenylacetylglutamine (1 part) and phenylacetic
  • the dosages for sodium salt phenylacetylglutamine are from 2.0 g to 120 g/day, preferably 70 g/day.
  • the dosages for phenylacetylisoglutamine are from 2.0 g to 30 g/day, preferably 14 g/day.
  • the dosages for intravenously administered sodium salt of phenylacetic acid are from 8.0 g to 40 g/day, preferably 24 g/day.
  • the compound may be provided in a composition that protects it from the acidic environment of the stomach.
  • the compound can be orally administered in combination with an antacid formulation.
  • the composition can also be administered in an enteric coating that maintains its integrity in the stomach and releases the active compound in the intestine.
  • Oral compositions will generally include an inert diluent or an edible carrier. They may be enclosed in gelatin capsules or compressed into tablets.
  • the active compound can be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups or the like.
  • Pharmaceutically compatible binding agents and/or adjuvant materials can be included as part of the composition.
  • the active compounds can also be mixed with other active materials that do not impair the desired action, or with materials that supplement the desired action, including other HIV antiviral agents such as AZT.
  • Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • the parental preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.
  • preferred carriers are physiological saline or phosphate buffered saline (PBS).
  • the patient is a 34-year-old white male who complained of recurrent infections.
  • the patient was practicing homosexual lifestyle. This patient was in reasonable health until January 1989 when he was found to be HIV positive. The symptoms of the disease he had since then were recurrent upper respiratory infections and Herpes zoster infection in January 1990.
  • August 1989 he began treatment with zidovudine. After initial improvement, his T4 cell count began to decease (from 741/mm3 on December 12, 1989 to 608/mm3 on March 6, 1990 and 420/mm3 on April 23, 1990).
  • T8 cell count after initial decrease, continued to increase. His T8 cell count on December 12, 1989 was 836/mm3 and 969/mm3 on March 6, 1990 and 1420/mm3 on April 23, 1990. After initial increase, T4/T8 ratio began to decrease (0.88 on December 12, 1989, 0.62 on March 6, 1990 and 0.30 on April 23, 1990).
  • T4 cell count (420/mm3 on April 23, 1990, 450/mm3 on May 21, 1990 and 480/mm3 on May 29, 1990).
  • T8 cell count continued to decrease (1420/mm3 on April 23, 1990, 1080/mm3 on May 21, 1990, 848/mm3 on May 29, 1990).
  • T4/T8 ratio continues to increase (0.30 on April 23, 1990, 0.42 on May 21, 1990, 0.56 on May 29, 1990). Normal values for T8 count are from 250/mm3 to 750/mm3 and T4/T8 ratio is more than 0.9.
  • the continuous increase of T4 cell count, decrease of T8 cell count and increase of T4/T8 ratio indicates objective improvement.
  • the patient is a 29-year-old male who was complaining of shortness of breath, cough, night sweats, fever and loss of 25 pounds of weight within three weeks before coming under my treatment.
  • This patient was in good health until the beginning of April 1990 when he was diagnosed with Hodgkin's disease of mixed cellularity.
  • the diagnosis was based upon the biopsy of the cervical lymph node. The patient was found to have enlargement of liver and spleen and multiple lymph nodes in the neck, chest and the abdomen. The bone marrow biopsy was highly suggestive of involvement with Hodgkin's disease.
  • the laboratory test done at the beginning of the treatment for Hodgkin's disease indicated HIV infection which prompted the final diagnosis of Hodgkin's disease, stage IV associated with AIDS.
  • the patient associated his HIV infection with intravenous use of narcotics. He did not receive any previous treatment for AIDS and Hodgkin's disease.
  • This patient began the treatment with Antineoplaston A10, 100 mg/ml intravenous infusions on April 23, 1990.
  • the dose of the formulation was gradually increased to 70g IV daily.
  • Antineoplaston AS2-1 100 mg/ml infusions were added to the treatment and the dosage of this formulation was gradually increased to 20g/24h.
  • the treatment was given in the form of continuous infusions through ambulatory pump.
  • the complete evaluation performed on June 22, 1990 revealed marked improvement in the patient's condition. The patient was feeling very well and did not have any complaints.
  • the liver and spleen were no longer enlarged by physical examination.
  • the laboratory tests on May 17, 1990 revealed T4 cell count of 82/mm3.
  • the repeated test on June 4, 1990 revealed marked increase of T4 cell count to 133/mm3.
  • the increase of T4 cell count indicates improvement in the treatment of AIDS.
  • the patient is a 32-year-old white male who was complaining of fever and night sweats. This patient was in good health until approximately 1985 when he was diagnosed as HIV positive. He did not use intravenous drugs, and most likely, his infection was due to homosexual contact. He did not have any treatment until June 8, 1990 when he was started on zidovudine. Before beginning the treatment with Antineoplaston AS2-1, his T4 cell count was decreasing and T8 cell count was increasing.
  • the patient began treatment with Antineoplaston AS2-1, 500 mg capsules on June 11, 1990. The patient was advised to take three capsules of Antineoplaston AS2-1 four times daily with meals. The treatment was tolerated very well without side effects.
  • the most recent blood test of July 30, 1990 revealed increase of T4 cell count and decrease of T8 cell count. Helper/suppressor ratio increased. His pre-treatment T4 cell count of June 8, 1990 was 496/mm3. Subsequent T4 cell counts were as follows: 484/mm3 on July 9, 1990 and 546/mm3 on July 30, 1990. Pretreatment T8 cell count on June 8, 1990 was 2232/mm3. The following T8 cell counts were 1430/mm3 on June 9, 1990 and 1281/mm3 on July 30, 1990. T4/T8 ratio increased from initial 0.22 on June 8, 1990 to 0.33 on July 9, 1990 and 0.42 on July 30, 1990.

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  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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  • Hydrogenated Pyridines (AREA)

Claims (7)

  1. Die Verwendung einer aktiven Verbindung der Formel
    Figure imgb0009
        worin R OH, NH₂, OW oder H ist;
       X H, F, Cl, Br, I, OH, OW, NO₂ oder NH₂ ist;
       Y H, F, Cl, Br oder I ist;
       W
    Figure imgb0010
     oder eine C₁- bis C₁₂-aliphatische Gruppe ist;
       Z eine aliphatische oder aromatische Gruppe mit C₁ bis C₁₂ ist;
       X und Y beide in der Verbindung variieren können; oder
    pharmazeutisch annehmbarer Salze derselben, zur Herstellung eines Arzneimittels für die therapeutische und/oder prophylaktische Behandlung von AIDS in einem befallenen Wirtsorganismus.
  2. Die Verwendung von 3-[N-Phenylacetylaminopiperidin]-2,6-dion oder seiner pharmazeutisch annehmbaren Salze zur Herstellung eines Arzneimittels für die therapeutische und/oder prophylaktische Behandlung von AIDS in einem befallenen Wirtsorganismus.
  3. Die Verwendung einer aktiven Verbindung der Formel
    Figure imgb0011
     oder Mischungen derselben,
       worin R OH, NH₂, OW oder H ist;
       X H, F, Cl, Br, I, OH, OW, NO₂ oder NH₂ ist;
       Y H, F, Cl, Br oder I ist;
       W
    Figure imgb0012
     oder eine C₁- bis C₁₂-aliphatische Gruppe ist;
       Z eine aliphatische oder aromatische Gruppe mit C₁ bis C₁₂ ist;
       X und Y beide in der Verbindung variieren können; oder
    pharmazeutisch annehmbarer Salze derselben, zur Herstellung eines Arzneimittels für die therapeutische und/oder prophylaktische Behandlung von AIDS in einem befallenen Wirtsorganismus.
  4. Die Verwendung einer aktiven Verbindung der Formel
    Figure imgb0013
        worin R OH, NH₂, OW oder H ist;
       X H, F, Cl, Br, I, OH, OW, NO₂ oder NH₂ ist;
       Y H, F, Cl, Br oder I ist;
       W
    Figure imgb0014
     oder eine C₁- bis C₁₂-aliphatische Gruppe ist;
       Z eine aliphatische oder aromatische Gruppe mit C₁ bis C₁₂ ist;
       X und Y beide in der Verbindung variieren können; und
    pharmazeutisch annehmbarer Salze derselben, als eine zusätzliche Komponente bei der Herstellung eines Arzneimittels nach Anspruch 3.
  5. Die Verwendung nach Anspruch 3, wobei die aktive Verbindung Phenylacetylglutamin, Phenylacetylisoglutamin, Mischungen derselben oder pharmazeutisch annehmbare Salze derselben ist.
  6. Die Verwendung nach Anspruch 3, wobei die aktive Verbindung eine Zusammensetzung ist, die ein 4:1-Verhältnis von Phenylacetylglutamin und Phenylacetylisoglutamin umfaßt.
  7. Die Verwendung nach Anspruch 3, wobei die aktive Verbindung eine Zusammensetzung ist, die Phenylessigsäure oder ihre pharmazeutisch annehmbaren Salze umfaßt.
EP91917237A 1990-09-04 1991-08-21 Pharmazeutische zusammensetzungen zur aids-behandlung Expired - Lifetime EP0500905B1 (de)

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US577464 1990-09-04
US07/577,464 US5089508A (en) 1990-09-04 1990-09-04 Methods for treating aids
PCT/US1991/005977 WO1992004027A1 (en) 1990-09-04 1991-08-21 Pharmaceutical compositions for use in treating aids

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EP0500905B1 true EP0500905B1 (de) 1996-03-13

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AT (1) ATE135217T1 (de)
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DK (1) DK0500905T3 (de)
ES (1) ES2084181T3 (de)
GR (1) GR3019970T3 (de)
SG (1) SG81889A1 (de)
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ZA (1) ZA916977B (de)

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Publication number Priority date Publication date Assignee Title
US5244922A (en) * 1990-09-04 1993-09-14 Burzynski Stanislaw R Methods for treating viral infections
DE59101214D1 (de) * 1991-07-15 1994-04-21 Artesan Pharma Gmbh Verwendung der Ascorbinsäure zur Zubereitung von Arzneimitteln zur Anwendung im Genitalbereich.
US5646182A (en) * 1992-06-15 1997-07-08 Burzynski; Stanislaw R. Methods for treating autoimmune diseases
DE4320201A1 (de) * 1993-06-18 1995-01-12 Asta Medica Ag Verwendung von Cetrorelix und weiteren Nona- und Dekapeptiden zur Herstellung eines Arzneimittels zur Bekämpfung von Aids und zur Wachstumsstimulation
DE69734713T2 (de) * 1996-05-14 2006-07-06 Burzynski, Stanislaw R., Houston Liposomale antineoplaston therapie mit bemerkenswert verbesserter antineoplastischer aktivität
US6127419A (en) * 1998-11-23 2000-10-03 Burzynski; Stanislaw R. Phenylacetic acid compositions for treating or preventing atherosclerosis and restenosis

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US4470970A (en) * 1981-07-02 1984-09-11 Burzynski Stanislaw R Purified antineoplaston fractions and methods of treating neoplastic disease
US4558057A (en) * 1981-12-15 1985-12-10 Burzynski Stanislaw R Purified antineoplaston fractions and methods of treating neoplastic disease
US4427684A (en) * 1982-09-24 1984-01-24 Ores Richard O Treatment and prevention of infection with herpes simplex and related viruses
GB2181346B (en) * 1985-09-11 1989-10-04 Nat Res Dev Pharmaceutical compositions and medical uses of dioxopiperidine derivatives
US4705796A (en) * 1986-08-25 1987-11-10 Stereochemical Genetics, Inc. Use of 3-N-phenylacetylamino-2,6-piperidinedione for treatment of neuropsychiatric disorders
DE3814549A1 (de) * 1987-10-30 1989-05-18 Bayer Ag N-substituierte derivate von 1-desoxynojirimycin und 1-desoxymannonojirimycin, verfahren zu deren herstellung und deren verwendung in arzneimitteln

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol.105, no. 19, 10 November 1986, Columbus, Ohio, US, abstract no. 164561W; BURZYNSKI S.R.: "Preclincal studies on antineoplaston A10 injections", page 27 *
Chemical abstracts, vol.105, no.19, 10/11/1986, Columbus, Ohio, US., abstract no. 164562x; ASHRAF A.Q. et al.: "Preclinical studies on Antineoplaston A10 injections", page 27 *

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WO1992004027A1 (en) 1992-03-19
ATE135217T1 (de) 1996-03-15
DE69117923T2 (de) 1996-08-01
GR3019970T3 (en) 1996-08-31
ZA916977B (en) 1992-06-24
DE69117923D1 (de) 1996-04-18
DK0500905T3 (da) 1996-08-05
SG81889A1 (en) 2001-07-24
ES2084181T3 (es) 1996-05-01
AU638869B2 (en) 1993-07-08
EP0500905A1 (de) 1992-09-02
AU8539791A (en) 1992-03-30

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